(187j) 3D Printing and Robotic Filling of Multi-Compartment Capsular Devices for Oral Drug Delivery

Therapies involving the oral administration of multiple drugs that either are mutually incompatible or interact in the gastrointestinal tract would benefit from the availability of multi-compartment capsular devices. These systems would simplify the dosing schedule and enhance patient compliance. Particularly, our technology enables efficient fabrication of fixed-dose combination products in small, personalized batches.

In the research work here presented, fabrication of capsule parts and relevant filling have been described. The devices under development comprise a modular structure resulting in the presence of multiple independent compartments. Each of them could be filled with various drugs and with a range of strengths/formulations of the same active component. Moreover, the release behavior of a single compartment would mainly depend on the composition and thickness of its walls. Therefore, by adjusting these parameters, the release performance of each compartment can be modified without affecting the properties of the joint compartments, thus yielding multiple release kinetics in a single unit.

By enabling the separation of the development of the capsule shell from the drug formulations conveyed, these systems would also ease time to market of new products.

In this respect, two-compartment capsular devices composed of three parts were initially developed. More into detail, capsule shells comprising 400 µm-thick and 800 µm-thick compartments were fabricated using 3D printing by fused deposition modeling (FDM), starting from hydroxyl propyl cellulose (Klucel™ LF). This required the development of i) an extrusion plant for manufacturing of filament suitable for 3D printing and of ii) an industrial-grade FDM equipment, both compliant with the strict requirements of the field of interest. In both cases, identification of the critical operating parameters that would affect the quality attributes of the final product were performed, together with the definition of suitable in-process controls. We assessed the stability of the starting polymer after hot processing, ruling out possible contaminations and formation of any hazardous products. The results obtained confirmed that extruded filaments and printed prototypes meet the specifications set.

Once filled and assembled, the two-compartment capsular devices showed the expected two-pulse release behavior, consistent with characteristics of the starting material employed. Furthermore, dimensional and release characteristics of multi-compartment capsules prepared by FDM turned out analogous to those produced by injection molding. Both represent interesting manufacturing techniques, for either rapid and inexpensive fabrication of small on-demand batches or relevant large-scale production.

A purposely developed robotic system, based on automated filling modules working simultaneously and in parallel, was employed for filling each compartment with specific formulations. Cross-contamination was avoided by enclosing each filling station in a dedicated clean room and by employing a robotic arm to move the capsular devices form one filling station to the next. The performance of the filling stations was evaluated during preliminarily filling trials with powders having diverse particle size and bulk density.

This level of personalization required innovative, non-destructive controls in order to guarantee the quality of the products in a cost-effective manner. Quality control machines able to check the thickness and weight of the capsule parts during the process have been developed. Spectroscopic techniques are also going to be implemented to confirm the identity of formulations to be used for filling.